期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 104, 期 22, 页码 9434-9439出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.0603523104
关键词
neurodegenerative; LRP-6; single-nucleotide polymorphism; APOE; Wnt
资金
- MRC [G0701075] Funding Source: UKRI
- Medical Research Council [G0701075] Funding Source: researchfish
- Medical Research Council [G0701075] Funding Source: Medline
- NIA NIH HHS [U24 AG021886] Funding Source: Medline
- NIMH NIH HHS [U01 MH046281, U01 MH 46290, U01 MH 46281, U01 MH 46372, U01 MH046290] Funding Source: Medline
Genome-wide linkage studies have defined a broad susceptibility region for late-onset Alzheimer's disease on chromosome 12, which contains the Low-Density Lipoprotein Receptor-Related Protein 6 (LRP6) gene, a coreceptor for Wnt signaling. Here, we report the association between common LRP6 variants and late-onset Alzheimer's disease in a multicenter case-control series as well as in a large family-based series ascertained by the National Institute of Mental Health-National Institute on Aging Genetics Initiative. As shown in the genome-wide linkage studies, our association depends mainly on apolipoprotein E-epsilon 4 (APOE-epsilon 4) carrier status. Haplotype tagging single-nucleotide polymorphisms (SNPs) with a set of seven allelic variants of LRP6 identified a putative risk haplotype, which includes a highly conserved coding sequence SNP: Ile-1062 -> Val. Functional analyses revealed that the associated allele Val-1062, an allele previously linked to low bone mass, has decreased beta-catenin signaling in HEK293T cells. Our study unveils a genetic relationship between LRP6 and APOE and supports the hypothesis that altered Wnt/beta-catenin signaling may be involved in this neuroclegenerative disease.
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